Mammalian genomes encode approximately 50 members of the nuclear hormone receptor superfamily, divided into roughly equal numbers of conventional receptors and orphan receptors. Many of the well characterized functions of the conventional receptors for steroids, thyroid hormone and other ligands are associated with maintenance of homeostasis in adults, but emerging information on the orphans have revealed unexpected and important developmental functions. We hypothesize that orphans have central roles in developmental signaling pathways, and the broad goal of this application is to characterize the functions of several orphans in various stages of organogenesis and other developmental processes. There are 4 individual projects, each based on the effects of loss of expression of a particular orphan. Orla Conneely will direct a project on the role of Nor-1 in development of the inner ear and also in bone and joint development. Austin Cooney will study the function of GCNF in pattern formation and mesoderm differentiation, particularly in early development. Sophia Tsai will direct a project on the role of COUP-TFII in prostate development And David Moore, the principal investigator, will direct a project on the developmental role of SHP, with a particular focus on its potential involvement in diabetes. These projects all depend on understanding the patterns of expression of the orphan receptors and their targets in both wild type and knockout or transgenic mice. Thus, they will rely heavily on both an Imaging and Histology core directed by Ming-Jer Tsai, and on an Animal core directed by Francesco DeMayo that will produce both knockout and transgenic animals. We believe that joining these efforts in this Program Project will strongly stimulate progress toward the overall thematic goal of establishing the relationship between these orphans and the conserved signaling pathways that control morphogenesis of multiple organ systems.